Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
  • B65B55/00—Preserving, protecting or purifying packages or package contents in association with packaging
  • B65B55/02—Sterilising, e.g. of complete packages
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
  • B65D1/00—Containers having bodies formed in one piece, e.g. by casting metallic material, by moulding plastics, by blowing vitreous material, by throwing ceramic material, by moulding pulped fibrous material, by deep-drawing operations performed on sheet material
  • B65D1/02—Bottles or similar containers with necks or like restricted apertures, designed for pouring contents
  • B65D1/0207—Bottles or similar containers with necks or like restricted apertures, designed for pouring contents characterised by material, e.g. composition, physical features

Definitions

• the invention relates to a process for manufacturing a sterilized package for a pharmaceutical product, particularly a dropper bottle assembly used to dispense liquids, aerosols or strings.
• Particularly dropper bottle assemblies are used to dispense a variety of liquids, typically one drop at a time.
• a liquid reagent used in laboratories, dispensing eye medication, dispensing ear medication, dispensing nose medication, or in any other environment where dispensing of a liquid in controlled drop increments is desired.
• a typical prior art bottle assembly comprises a plastic squeeze bottle, a nozzle tip or dropper which is snap fit into the bottle and a cap or closure which is threaded onto the bottle. Liquid is dispensed one drop at a time by squeezing the bottle so as to force liquid out the end of the nozzle tip.
• the bottle, the nozzle tip and the cap are made of low density polyethylene (the abbreviation PE is also used instead of polyethylene hereinafter) because this material has a high enough modulus of elasticity for squeezing the cylindrical sidewall of the bottle with one's fingers which causes the liquid therein to pass through a passageway.
• PE low density polyethylene
• the bottle For filling the bottle with a pharmaceutical product, particularly an ophthalmic liquid which has to fulfill the conditions concerning sterility, it is state of the art to filtrate and to sterilize the solution or liquid which should be filled into the bottles by filtration or autoclaving. Also the bottles, the nozzle tips and the caps are sterilized, e.g. by ethylene oxide treatment, UV, gamma or electron beam irradiation. The filling of the bottles takes place in aseptic room conditions. However, after filling the bottles, inserting the nozzle tip into the neck portion and threading the cap onto the bottle no further sterilization will proceed. The filled and closed bottles are removed from the aseptic area.
• the aseptic area is normally a room which stands under slight excess air pressure and the entrance and the exit of the room are constructed as sluices.
• a pharmaceutical product as used hereinbefore or hereinafter is understood to relate in particular to a pharmaceutical composition, which is preferably an aqueous and/or a non-aqueous pharmaceutical composition or a mixture of a non-aqueous and an aqueous pharmaceutical composition, which is preferably a liquid solution, a gel or an ointment, wherein pharmaceutical relates preferably to an ophthalmic, an otic and/or a nasal administration.
• a pharmaceutical composition which is preferably an aqueous and/or a non-aqueous pharmaceutical composition or a mixture of a non-aqueous and an aqueous pharmaceutical composition, which is preferably a liquid solution, a gel or an ointment, wherein pharmaceutical relates preferably to an ophthalmic, an otic and/or a nasal administration.
• EP-A-0 322 134 describes the terminal overpressure steam sterilization of a blister package comprising a squeeze-type polypropylene (hereinafter also PP) bottle filled with a pharmaceutical composition. It furthermore teaches that the bottles to be sterilized are filled to create a slight overflow of the pharmaceutical composition in order to eliminate any air entrapped into the bottle because it would produce a pressure greater than the overpressure created during the steam sterilization cycle.
• PP polypropylene
• the present invention addresses the problem of providing a pharmaceutical package, particularly a bottle assembly filled with a pharmaceutical product, particularly an ophthalmic solution or gel, which meets the requirements of the European Pharmacopoeia regulation and/or EU-regulation without any significant deformation and retaining a sufficient squeezability for dispensing the liquid after the autoclaving proceedings.
• the use of a specific form of polypropylene for the material of the package enables to fulfill the European Pharmacopoeia regulation and/or EU regulation.
• Packages made of a specific form of polypropylene are heat-resistant and retain their formation and their squeezing characteristics after the autoclaving processing. Therefore, the consumer can easily dispense one drop at a time by squeezing the package so as to force the pharmaceutical product out of the package.
• the invention provides a dropper bottle assembly with a high enough squeezability for dispensing an ophthalmic solution or gel by compressing the bottle.
• An example of the invention is a dropper bottle assembly which comprises a squeeze bottle having a nozzle tip designed to snap fit within the neck portion of the bottle, and a cap designed to fit over the nozzle tip and engage a threaded portion of the neck portion.
• the nozzle tip has a passageway for allowing fluid within the bottle to be dispensed through an outlet. Liquid is dispensed by first removing the cap and then squeezing the cylindrical sidewall of bottle with one's fingers which causes the liquid therein to pass through the passageway.
• the bottle assembly is further provided with either a shrink collar or with a temper resistance ring.
• the bottle is made of a specific form of polypropylene, particularly a polypropylene of the type Appryl®3020 SM 3.
• the bottle has a similar shape with the exception that the bottom has advantageously a concave configuration. This is in particular for avoiding deformation, e.g. shrinkage or blowing-up, of the bottle during the autoclaving processing. Due to the concave configuration the degree of pressure necessary to cause deformation of the bottom is much higher. Naturally, other indentation, grooves, slits or slots can be designed at the bottom or the sidewall to give the bottle a greater stability during the autoclaving processing.
• the nozzle tip is also particularly formed of a specific form of polypropylene, particularly a polypropylene of the type Appryl®3020 SM 3.
• polypropylene is a quite rigid material and it is more difficult to snap fit the nozzle tip into the neck portion of the bottle
• the nozzle tip has a special configuration to ensure a good seal between the bottle and the nozzle tip.
• the sealing part of the nozzle tip used for sticking the nozzle tip into the neck portion of the bottle is formed in the upper part nearly cylindrical whereas the lower part has the form of a taper shank.
• the sealing part of the nozzle tip is provided with a collar.
• the cap is threaded on the neck portion of the bottle having external threads.
• the cap as the closure of the bottle assembly can also be made of polypropylene, however, the cap is preferably made of another material than polypropylene and/or a material chosen such, that these two materials have a different modulus of elasticity.
• the wall thickness of the PP bottle is typically in the range of 0.3 mm to 0.6 mm, preferably 0.45 mm. If the wall thickness is too thin, then the stability of the bottle decreases. However, if the wall thickness is too thick, then the squeezability of the bottle decreases and the bottle becomes too rigid. Indeed, the preferable value of the wall thickness is lower than in comparison with the prior art PE bottles, so that there is much lesser material necessary for molding the bottles, preferably by an injection molding process.
• the closed bottles are introduced into an autoclaving chamber.
• filling of the bottles denotes typically a normal filling, such that for example in the upper part of said bottle some air will remain, as distinguished from prior art wherein the bottles to be sterilized are filled to create a slight overflow of the pharmaceutical composition in order to eliminate any air entrapped into the bottle.
• the whole bottles will be sterilized it is not anymore necessary that the filling and closing of the bottles has to take place under aseptic conditions.
• such an autoclaving chamber works with steam.
• the temperature and the pressure run in the chamber as a function of time.
• the chamber contains typically one or more nozzles for the steam entrance and typically several sensors for temperature monitoring.
• the temperature can be adjusted very quickly if some corrections might be necessary.
• the chamber is provided with a pressure device for generating a counter pressure in the autoclaving chamber.
• the pressure can be adjusted very quickly if some corrections might be necessary.
• the counter pressure is regulated electronically via computer control. Said pressure set-up is advantageously used for avoiding a blowing-up of the bottles. After introducing the bottles into the chamber, the temperature rises typically from room temperature to 121 °C and the pressure rises typically from atmospheric pressure to a maximum value which is characteristic for the sterilization process. Typically, the choice of the pressure value depends on the form of the bottles.
• the adjusted pressure with a value of 2700 mbar is lower for the 5 ml bottles than for the 10 ml bottles with a value of 3200 mbar.
• a lower pressure value is necessary to avoid blowing up of the bottles.
• the increasing of the temperature is quite steep, whereas the gradient of the pressure remains nearly constant up to reaching the maximum value.
• the values of the temperature and the pressure maintain constant. After the sterilization both the temperature and the pressure decreases continuously.
• the autoclaving processing takes as a whole nearly one hour. After reaching again room temperature and atmospheric pressure the chamber will be opened for taking out the sterilized bottles.
• the invention provides a package particularly a dropper bottle assembly for pharmaceutical products, especially for ophthalmic pharmaceutical solutions and gels which can be sterilized as a whole after filling the product into the package by an autoclaving process in accordance to the invention.
• the package retains after the autoclaving procedure its squeezability which is important for the consumer for dispensing especially a solution or gel out of the package. Furthermore, no deformation could be observed after having exposed said package to an autoclaving process in accordance to the invention.
• a package according to the invention especially a dropper bottle assembly filled with an ophthalmic solution, gel or ointment, fulfills the European Pharmacopoeia, 3rd. edition (1997), and/or the EU regulation mentioned above, which ensure a higher level of safety.
• the PP-material used for fabricating the package in accordance to the invention exhibits physical chemical properties which meet the requirements laid down in the supplement of 1998 of the European Pharmacopoeia, 3rd edition (1997). This is in particular applicable to the additives comprised in the PP-material in accordance to the invention.

Landscapes

• Engineering & Computer Science (AREA)
• Mechanical Engineering (AREA)
• Ceramic Engineering (AREA)
• Medical Preparation Storing Or Oral Administration Devices (AREA)
• Packages (AREA)
• Auxiliary Devices For And Details Of Packaging Control (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Apparatus For Disinfection Or Sterilisation (AREA)
• Making Paper Articles (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Food Preservation Except Freezing, Refrigeration, And Drying (AREA)
• Containers And Plastic Fillers For Packaging (AREA)
• Containers Having Bodies Formed In One Piece (AREA)
• Medicinal Preparation (AREA)
• Containers And Packaging Bodies Having A Special Means To Remove Contents (AREA)

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Citations (5)

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• 2000
  • 2000-05-26 WO PCT/EP2000/004828 patent/WO2000073156A1/en active IP Right Grant
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  • 2000-05-26 EP EP00929561A patent/EP1181197B1/de not_active Expired - Lifetime
  • 2000-05-26 JP JP2000621239A patent/JP2003500302A/ja active Pending
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• 2001
  • 2001-10-09 US US09/973,256 patent/US7051906B2/en not_active Expired - Fee Related
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• 2002
  • 2002-07-18 HK HK02105329.9A patent/HK1045290B/zh not_active IP Right Cessation
• 2007
  • 2007-07-24 US US11/782,511 patent/US20080019863A1/en not_active Abandoned

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